The goal of the proposed study is to explore the potential therapeutic benefit of a novel approach to rehabilitation of motor control of the paretic distal upper limb in stroke survivors. This multimodality treatment combines administration of a pharmacological agent for reducing unwanted neuromuscular hyperexcitability with a training paradigm focused on expanding exploration of the muscle activation workspace. In our previous research, we have observed striking deficits in the generation of proper muscle activation patterns in the hand. Motoneuronal hyperexcitability, especially of the long finger-flexors, is readily apparent, as is a diminished capacity to appropriately modulate activation patterns according to task. The proposed study would directly address these complications. Accordingly, we will pursue the following aims: Aim 1: Determine the extent to which anti-serotonergic agents outperform conventional medications in reducing hyperexcitability post-stroke without impacting voluntary activation or alertness. Tizanidine hydrochloride, a clinically administered anti-spasticity medication, has been shown to effectively reduce motoneuron hyperexcitability, presumably through noradrenergic pathways, but causes serious side effects including somnolence. In preliminary studies we identified a promising alternative drug, the anti-serotonergic agent cyproheptadine hydrochloride, which was able to reduce hyperexcitability without reducing voluntary strength for single doses. We will compare the effects of tizanidine and cyproheptadine at chronic dosages. We hypothesize that: cyproheptadine will be more effective than tizanidine in reducing unwanted hyperexcitability without diminishing strength or increasing somnolence. Aim 2: Assess the efficacy of using a multimodality intervention combining monoaminergic agents with upper extremity training. We anticipate that combining administration of the monoaminergic drug found effective in Aim 1 to reduce flexor hyperexcitability with focused training to alter muscle activation patterns will facilitate rehabilitation. Two different training techniques will be compared, one focusing directly on the training of muscle activation patterns through a custom computer game and the other utilizing a novel occupational therapy training protocol. We hypothesize that: the combined therapy of the drug with the training will lead to greater functional improvement over either drug administration or therapeutic training alone. Further, we hypothesize that: for the groups receiving multimodal training, improvements in motor control, will be greater for those training with the electromyographically controlled computer games. The proposed study is aimed at contributing to the establishment of new techniques for maximizing recovery of motor function of the paretic upper limb post-stroke, especially in individuals with more severe distal impairment. The results of this study will have immediate import for clinical practice for stroke rehabilitation.